Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Chromosome “lassoing”: A new key mechanism in cell division

09.05.2008
Scientists at the IFOM-IEO Campus have revealed the function of a protein that is indispensable for passing on an accurate copy of the genome from mother to daughter cells. This study, published in Cell, opens up new avenues of research to reduce the toxicity of chemotherapy in the treatment of cancer.

The protein can be compared to a cowboy’s lasso: it catches chromosomes and ties them to a transitory structure assembled during cell division. Once they have been neatly tied up, the chromosomes await the end of replication to be equally distributed between the two daughter cells.

But if the lasso doesn’t catch them, chromosomes end up being randomly scattered, with potentially disastrous genetic effects: should cells survive this, they receive the wrong genetic inheritance, with dire consequences. The structure and function of this chromosomal lasso were discovered in Milan, at the IFOM-IEO Campus (that hosts the laboratories of the FIRC Institute of Molecular Oncology Foundation – IFOM – and of the European Institute of Oncology – IEO) and these findings have just been published in the prestigious scientific journal, Cell.

“We’ve been studying a molecule called Ndc80 – explains Andrea Musacchio, principal author of the study, and head of a research group in the Department of Experimental Oncology (IEO). This protein is a key player necessary for the correct distribution of genetic inheritance. Ndc80 could potentially be used as a target for new drugs that would have fewer toxic side-effects than current drugs, such as paclitaxel (originally called taxol), which mainly act as inhibitors of cell replication.” The operative word here is ‘mainly’. Although many drugs used in traditional chemotherapy act on molecular targets that are in involved in the duplication of cells (during a phase known as ‘mitosis’), these targets also have other cellular functions. Ndc80, on the other hand, performs its job only during mitosis.

So, by blocking Ndc80, the only cells that would be affected would be the dividing ones. Any other cells would be unaffected. Musacchio and his colleagues (together with co-author Peter De Wulf and his research team) are already testing a number of substances that might be able to block the action of Ndc80. The published findings were a truly international effort involving research groups from England and the USA; much of the work was made possible thanks to financial support from the Italian Association for Cancer Research (AIRC).

MITOSIS AND CHEMOTHERAPY TREATMENT FOR CANCER

“We’ve been studying the mechanisms that regulate accurate genome duplication for many years now – explains Musacchio. Our hope is to discover new, less toxic drugs for chemotherapy. Cancer cells grow at a much faster rate than normal cells and traditional chemotherapy drugs, like paclitaxel, block this cell division process. The efficacy of these drugs depends on differences in the growth rates of normal and cancer cells. This means that paclitaxel is toxic for all cells undergoing mitosis; however, since most mitotic cells in cancer patients are actually cancer cells, it follows that this drug will do most of its damage in cancer cells. The problem is that paclitaxel acts on proteins that are essential not only for cells to divide, but also for other phases of the cell cycle. This means that the drug has significant associated toxicity, something we would rather avoid. We had hypothesized that Ndc80 was only active during cell division, which is why we thought it might be an interesting target to study. And our results proved us right. We discovered that Ndc80 acts as a kind of molecular lasso that tethers chromosomes to the mitotic spindle, a molecular structure that only forms during mitosis. Ndc80 straps chromosomes firmly onto the spindle until the dividing cells separate; after this stage, it is of no more use to the cell. So, if we interfere with Ndc80, we can significantly reduce the so-called ‘toxicity window’.” Any drug that inhibits the function of Ndc80 would therefore be much more tumor-specific than currently available treatments. “Peter De Wulf and I – continues Musacchio – have already flagged some interesting molecules. Our in vitro work now needs to be validated in vivo, first in laboratory models, and then in standard clinical trials.”

CHANGING STRATEGY: FROM THERAPEUTIC TARGETS TO THERAPEUTIC DRUGS

Musacchio and colleagues have made an important step forward in understanding the molecular workings of normal and cancer cells. This work is the starting point for the development of new drugs. But, as this scientist points out, the expertise needed to achieve this latter step is sorely lacking in Italian academic research environments. “The development of new drugs – explains Musacchio – depends on the mutual interaction of Chemists and Biologists. Italian academic research still hasn’t capitalized on this, and academia limits itself to the identification of therapeutic targets. While this is a necessary and important step, the development of new drugs is left in the hands of the large pharmaceutical companies.”

This situation is unacceptable. Italian academic research (which is, by definition free, and not profit-led) can – and should – also focus on screening for molecules that can interact with newly-identified targets to inhibit them. To add insult to injury, such compounds are often neglected by pharmaceutical companies, when they do not fall within their production strategies. Musacchio and De Wulf’s strategy in their hunt for molecules that can inhibit Ndc80, exemplifies what needs to be done. But, unfortunately, their approach is not commonly adopted in Italy, and the gap between basic and translational or applied research grows ever wider. Musacchio uses a vivid metaphor to describe the situation: “We discover mountains to climb, but we don’t have the equipment needed to guarantee the success of our expeditions”. We shouldn’t underestimate the value of the collections of compounds hidden away in academic chemistry laboratories; these could be made publicly available. Mussacchio concludes: “A contribution of this kind would be invaluable for international research and a crowning achievement for our Nation”.

AN INTERNATIONAL COLLABORATION

The findings are the result of a collaborative effort between the IFOM-IEO Campus and the University of North Carolina (USA), Colorado State University (USA), the Sir William Dunn School of Pathology (UK), the Wellcome Trust Centre for Cell Biology at the University of Edinburgh (UK) and the University of London (UK). The research was funded not only by AIRC, but also by the International Association for Cancer Research, the Telethon Foundation and the Italian Ministry of Health.

Francesca Noceti | alfa
Further information:
http://www.ifom-ieo-campus.it/

Further reports about: Musacchio Ndc80 Paclitaxel Protein chemotherapy chromosomes lasso toxic

More articles from Life Sciences:

nachricht Rochester scientists discover gene controlling genetic recombination rates
23.04.2018 | University of Rochester

nachricht One step closer to reality
20.04.2018 | Max-Planck-Institut für Entwicklungsbiologie

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Molecules Brilliantly Illuminated

Physicists at the Laboratory for Attosecond Physics, which is jointly run by Ludwig-Maximilians-Universität and the Max Planck Institute of Quantum Optics, have developed a high-power laser system that generates ultrashort pulses of light covering a large share of the mid-infrared spectrum. The researchers envisage a wide range of applications for the technology – in the early diagnosis of cancer, for instance.

Molecules are the building blocks of life. Like all other organisms, we are made of them. They control our biorhythm, and they can also reflect our state of...

Im Focus: Spider silk key to new bone-fixing composite

University of Connecticut researchers have created a biodegradable composite made of silk fibers that can be used to repair broken load-bearing bones without the complications sometimes presented by other materials.

Repairing major load-bearing bones such as those in the leg can be a long and uncomfortable process.

Im Focus: Writing and deleting magnets with lasers

Study published in the journal ACS Applied Materials & Interfaces is the outcome of an international effort that included teams from Dresden and Berlin in Germany, and the US.

Scientists at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) together with colleagues from the Helmholtz-Zentrum Berlin (HZB) and the University of Virginia...

Im Focus: Gamma-ray flashes from plasma filaments

Novel highly efficient and brilliant gamma-ray source: Based on model calculations, physicists of the Max PIanck Institute for Nuclear Physics in Heidelberg propose a novel method for an efficient high-brilliance gamma-ray source. A giant collimated gamma-ray pulse is generated from the interaction of a dense ultra-relativistic electron beam with a thin solid conductor. Energetic gamma-rays are copiously produced as the electron beam splits into filaments while propagating across the conductor. The resulting gamma-ray energy and flux enable novel experiments in nuclear and fundamental physics.

The typical wavelength of light interacting with an object of the microcosm scales with the size of this object. For atoms, this ranges from visible light to...

Im Focus: Basel researchers succeed in cultivating cartilage from stem cells

Stable joint cartilage can be produced from adult stem cells originating from bone marrow. This is made possible by inducing specific molecular processes occurring during embryonic cartilage formation, as researchers from the University and University Hospital of Basel report in the scientific journal PNAS.

Certain mesenchymal stem/stromal cells from the bone marrow of adults are considered extremely promising for skeletal tissue regeneration. These adult stem...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Invitation to the upcoming "Current Topics in Bioinformatics: Big Data in Genomics and Medicine"

13.04.2018 | Event News

Unique scope of UV LED technologies and applications presented in Berlin: ICULTA-2018

12.04.2018 | Event News

IWOLIA: A conference bringing together German Industrie 4.0 and French Industrie du Futur

09.04.2018 | Event News

 
Latest News

Structured light and nanomaterials open new ways to tailor light at the nanoscale

23.04.2018 | Physics and Astronomy

On the shape of the 'petal' for the dissipation curve

23.04.2018 | Physics and Astronomy

Clean and Efficient – Fraunhofer ISE Presents Hydrogen Technologies at the HANNOVER MESSE 2018

23.04.2018 | Trade Fair News

VideoLinks
Science & Research
Overview of more VideoLinks >>>